P672: CHARACTERISTICS AND OUTCOMES OF PATIENTS WITH CHRONIC MYELOID LEUKEMIA AND T315I MUTATION AFTER FAILURE OF PRIOR THERAPIES
Authors: Aram Bidikian, Fadi Haddad, Koji Sasaki, Ghayas Issa, Tapan Kadia, Nitin Jain, Yesid Alvarado, Nicholas Short, Musa Yilmaz, Lucia Masarova, Elias Jabbour, Hagop Kantarjian
Journal: HemaSphere (2023)

Background: Chronic myeloid leukemia (CML) with T315I mutation (T315Im) has been reported to have a poor prognosis. We have previously described the outcome of patients (pts) who develop T315Im following imatinib or second-generation tyrosine kinase inhibitors (TKIs). Aims: Herein we report the outcome of CML with T315Im in a larger cohort of 107 pts with CML and T31Im. Methods: We retrospectively reviewed 107 pts with CML in chronic phase (CP) or accelerated phase (AP) diagnosed between January 1991 and January 2022 and who later developed T315Im. Pts were divided into CP, AP, or blastic phase (BP) (according to MD Anderson criteria) at the time of T315Im detection. For this analysis, overall survival (OS) was defined from the date T315Im was first detected to the date of death or last follow-up. Results: A total of 107 pts were reviewed. Their median age was 49 years (range, 20-87). Their baseline characteristics are summarized in Figure 1. At the time of T315Im detection, 54 (51%) pts were in CP, 14 (13%) in AP, and 39 (36%) in BP. Twenty (19%) pts had composite ABL1 mutations, the most frequent being F317L (n=4), E255K (n=3), and V299L (n=2). The median number of therapies before the emergence of T315Im was 3 (range, 1-9). Most pts had received prior imatinib (n=80; 75%) and/or dasatinib (n=79; 74%). The median time from CML diagnosis to the emergence of T315Im was 41 months (range, 4-313) overall: 42 months (range, 7-313), 38 months (range, 8-159), and 27 months (range, 4-243) in pts with CP, AP, and BP at the time of T315Im, respectively (P=0.73). Of the 107 pts, 102 received subsequent therapy after T315Im was detected. 83 pts had T315Im repeat testing after therapy, of whom 37 (45%) cleared their mutation. Treatments that resulted in the clearance of T315Im were ponatinib (n=10; 27%), ASCT (n=10; 27%), omacetaxine (n=5; 14%), chemotherapy + TKI (n=4; 11%), asciminib (n=3; 8%), and other investigational agents (n=5; 14%). After a median follow-up of 75 months (range, 41-110) since T315Im was first detected, the median OS was 49 months (range, 26-73) and the 5-year OS was 44%. Pts with CML who remained in CP at the time of T315Im diagnosis had better survival compared with those in AP or BP, with a median OS of 132, 31, and 6 months, and 5-year OS of 70%, 37%, and 10%, respectively (P<0.001). Pts who cleared their T315Im after therapy had a 5-year OS of 70% from the time T315Im was diagnosed (median, 163 months) compared with 25% (median, 24 months) in those who did not (P<0.001). When we restricted the survival events to death due to CML, the median OS was 163 months (range, 69-257) and the 5-year CML-related OS was 64%. In the 37 pts who cleared their T315Im, numbers in each treatment group were small to draw firm conclusions. Nevertheless, CML-related deaths were observed in 1 of 10 (10%) pts treated with ponatinib, 2 of 5 (40%) pts treated with omacetaxine, and 3 of 5 (60%) pts treated with investigational agents; their 5-year OS rates since T315Im was first detected were 89%, 75%, and 60%, respectively. No CML-related deaths were observed among the 10 pts treated with ASCT, 4 pts treated with chemotherapy + TKI (without ASCT), and 3 pts treated with asciminib. Summary/Conclusion: Pts with CML who remain in CP at the time of T315Im may have an indolent disease course with a long-term OS of 70%. In contrast, those who develop T315Im in AP/BP tend to have poor outcomes. Newer-generation TKIs and novel agents are needed in pts with advanced phase T315m CML.Keywords: Resistance, Chronic myeloid leukemia, Imatinib resistance